title: Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function.
abstract: Naive CD8+ T cells rely upon oxidation of fatty acids as a primary source of energy. After antigen encounter, T cells shift to a glycolytic metabolism to sustain effector function. It is unclear, however, whether changes in glucose metabolism ultimately influence the ability of activated T cells to become long-lived memory cells. We used a fluorescent glucose analog, 2-NBDG, to quantify glucose uptake in activated CD8+ T cells. We found that cells exhibiting limited glucose incorporation had a molecular profile characteristic of memory precursor cells and an increased capacity to enter the memory pool compared with cells taking up high amounts of glucose. Accordingly, enforcing glycolytic metabolism by overexpressing the glycolytic enzyme phosphoglycerate mutase-1 severely impaired the ability of CD8+ T cells to form long-term memory. Conversely, activation of CD8+ T cells in the presence of an inhibitor of glycolysis, 2-deoxyglucose, enhanced the generation of memory cells and antitumor functionality. Our data indicate that augmenting glycolytic flux drives CD8+ T cells toward a terminally differentiated state, while its inhibition preserves the formation of long-lived memory CD8+ T cells. These results have important implications for improving the efficacy of T cell-based therapies against chronic infectious diseases and cancer.
authors.forename: Madhusudhanan
authors.initials: M
authors.lastname: Sukumar
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Yun
authors.initials: Y
authors.lastname: Ji
authors.forename: Murugan
authors.initials: M
authors.lastname: Subramanian
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Crompton
authors.forename: Zhiya
authors.initials: Z
authors.lastname: Yu
authors.forename: Rahul
authors.initials: R
authors.lastname: Roychoudhuri
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Palmer
authors.forename: Pawel
authors.initials: P
authors.lastname: Muranski
authors.forename: Edward D
authors.initials: ED
authors.lastname: Karoly
authors.forename: Robert P
authors.initials: RP
authors.lastname: Mohney
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Klebanoff
authors.forename: Ashish
authors.initials: A
authors.lastname: Lal
authors.forename: Toren
authors.initials: T
authors.lastname: Finkel
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
authors.forename: Luca
authors.initials: L
authors.lastname: Gattinoni
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D019496:Cancer Vaccines; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D003847:Deoxyglucose / Q000494:pharmacology; D004734:Energy Metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects*; D006593:Hexokinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007156:Immunologic Memory; D016233:Immunotherapy, Active; D008546:Melanoma, Experimental / Q000201:enzymology / Q000276:immunology* / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D013312:Stress, Physiological; D013601:T-Lymphocytes / Q000276:immunology; D047368:Tumor Burden
chemical_list: D019496:Cancer Vaccines; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D003847:Deoxyglucose; D006593:Hexokinase